Lung cancer is the leading cause of cancer death in the United States. Cure rates from primary treatment are low (approximately 15%). There is an urgent need to develop compounds, which can prevent the disease in individuals with a history of cigarette smoking and other factors associated with increased lung cancer risk. A number of compounds have been tested but trials to date have not resulted in a decrease of lung cancer incidence. In fact, two large-scale chemoprevention trials that evaluated beta-carotene in active and former smokers, resulted in an increase of incidence and mortality from lung cancer. Recently, the focus of lung cancer chemoprevention has shifted towards investigations using inhibitors of inflammatory response pathways and inhibitors of growth factor signaling pathways. A novel class of agents has been developed that induce apoptosis. Exisulind (Aptosyn) is the first agent in this class, and it has shown promise in chemoprevention of colorectal carcinoma by reducing the number of size of adenomatous polyps in humans. In animal studies, this agent has resulted in a reduction of carcinogen-induced lung cancer. To test the clinical utility of this agent in lung cancer prevention, we propose to perform a double-blind, placebo-controlled, randomized, clinical efficacy trial in former smokers. Participants will be stratified by lung cancer risk based on airway obstruction, prior history of completely resected stage I non-small cell lung cancer, and the histopathology of bronchial biopsies. They will be randomized 2:1 to drug vs. placebo. A surrogate marker of lung cancer, the proliferation marker Ki-67, will be used as the primary endpoint. Other markers previously and currently investigated by us and others (MCM2, hnRNP, apoptosis, cytokine response profiles, (epi) genetic alterations, morphology) will be explored as surrogate trial endpoints. Exisulind will be given orally at a dose of 500 mg daily for 6 months. With 93 evaluable participants randomized to exisulind, the study will have 80% power to detect a 50% or greater decrease in the mean Ki-67 labelling index as a result of treatment. Since we anticipate a 25% attrition rate, we are planning to enroll a total of 186 subjects over 4 years. Given the number of eligible subjects at our institution that already participate in early detection trials, we are confident that the goal of this proposed study can be achieved during the 5-years of funding. The data generated by these investigations will be important for future decisions on large-scale chemoprevention trials using disease incidence and mortality as endpoints.